Thienopyrimidines

ABSTRACT

Thienopyrimidines of the formula (I) and their physiologically acceptable salts, in which R 1 , R 2  and X are as defined in claim 1, exhibit phosphodiesterase V inhibition and can be employed for the treatment of illnesses of the cardiovascular system and for the treatment and/or therapy of impotence.

[0001] The invention relates to compounds of the formula I

[0002] in which

[0003] R¹ and R² are each, independently of one another, H, A, OH, OA,NO₂ or Hal,

[0004] R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,

[0005] X is mono-R⁵-substituted R³ or R⁴,

[0006] R³ is linear or branched alkylene having 1-10 carbon atoms, inwhich one or two CH₂ groups may be replaced by —CH═CH—groups, O, NH orNA,

[0007] R⁴ is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,

[0008] R⁵ is O(CH₂)_(n)COOH, O(CH₂)_(n)COOA, O(CH₂)_(n)CONH₂,O(CH₂)_(n)CONHA, O(CH₂)_(n)CONA₂ or O(CH₂)_(n)CN, S(O)_(m)(CH₂)_(n)COOH,S(O)_(m)(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)CONH S(O)_(m)(CH₂)_(n)CONHA,S(O)_(m)(CH₂)_(n)CONA₂ or S(O)_(m)(CH₂)_(n)CN,

[0009] m is 0, 1 or 2,

[0010] n is 1 or 2,

[0011] A is alkyl having 1 to 6 carbon atoms, and

[0012] Hal is F, Cl, Br or I,

[0013] and their physiologically acceptable salts and/or solvates.

[0014] Pyrimidine derivatives are disclosed, for example, in WO99/55708, EP 934321, EP 201 188 or WO 93/06104.

[0015] The invention had the object of finding novel compounds havingvaluable properties, in particular those which can used for thepreparation of medicaments.

[0016] It has been found that the compounds of the formula I and theirsalts and/or solvates have very valuable pharmacological properties andare well tolerated.

[0017] In particular, they exhibit specific inhibition of cGMPphosphodiesterase (PDE V).

[0018] Quinazolines having a cGMP phosphodiesterase-inhibiting activityare described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid.37, 2106(1994).

[0019] The biological activity of the compounds of the formula I can bedetermined by methods as described, for example, in WO 93/06104. Theaffinity of the compounds according to the invention for cGMP and cAMPphosphodiesterase is determined by measuring their IC₅₀ values(concentration of the inhibitor needed to achieve 50% inhibition of theenzyme activity).

[0020] The determinations can be carried out using enzymes isolated byknown methods (for example W. J. Thompson et al., Biochem. 1971, 10,311). The experiment can be carried out using a modified batch method ofW. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228).

[0021] The compounds are therefore suitable for the treatment ofillnesses of the cardiovascular system, in particular cardiacinsufficiency, and for the treatment and/or therapy of impotence(erectile dysfunction).

[0022] The compounds are furthermore suitable for the treatment ofangina, high blood pressure, high pulmonary pressure, congestive heartfailure, atherosclerosis, conditions involving reduced passage throughheart vessels, peripheral vascular diseases, strokes, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritablebowel syndrome, tumours, renal insufficiency, liver cirrhosis and forthe treatment of female sexual disorders.

[0023] The use of substituted pyrazolopyrimidinones for the treatment ofimpotence is described, for example, in WO 94/28902.

[0024] The compounds are effective as inhibitors ofphenylephrine-induced contractions in corpus cavernosum preparations ofrabbits. This biological action can be demonstrated, for example, by themethod described by F. Holmquist et al. in J. Urol., 150, 1310-1315(1993).

[0025] The inhibition of the contraction demonstrates the effectivenessof the compounds according to the invention for the therapy and/ortreatment of impotence.

[0026] The compounds of the formula I can be employed as medicamentactive ingredients in human and veterinary medicine. They canfurthermore be employed as intermediates for the preparation of furthermedicament active ingredients.

[0027] The invention accordingly relates to the compounds of the formulaI and to a process for the preparation of compounds of the formula Iaccording to claim 1 and their salts,

[0028] characterised in that

[0029] a) a compound of the formula II

[0030]  in which

[0031] X is as defined above,

[0032] and L is Cl, Br, OH, SCH₃ or a reactive esterified OH group,

[0033] is reacted with a compound of the formula III

[0034]

[0035]  in which

[0036] R¹ and R² are as defined above, or

[0037] b) a radical X in a compound of the formula I is converted intoanother radical X by, for example, hydrolysing an ester group to a COOHgroup or converting a COOH group into an amide or into a cyano group,

[0038] and/or in that a compound of the formula I is converted into oneof its salts.

[0039] Above and below, the radicals R¹, R² R³, R⁴, R⁵, X and L are asdefined under the formulae 1, II and III, unless expressly statedotherwise.

[0040] A is alkyl having 1-6 carbon atoms.

[0041] In the above formulae, alkyl is preferably unbranched and has 1,2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl,furthermore preferably isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

[0042] A is furthermore alkenyl having 2-6 carbon atoms, for examplevinyl or propenyl.

[0043] A is furthermore a halogenated alkyl radical, such as, forexample, trifluoromethyl.

[0044] X is a mono-R⁵-substituted R³ or R⁴ radical.

[0045] R³ is a linear or branched alkylene radical having 1-10 carbonatoms, where the alkylene radical is preferably, for example, methylene,ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene,pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene,1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene,1-ethyl-2-methylpropylene, 1,2- or 1,2,2-trimethylpropylene, linear orbranched heptylene, octylene, nonylene or decylene.

[0046] R³ is furthermore, for example, but-2-enylene or hex-3-enyleneVery particular preference is given to methylene, ethylene, propylene orbutylene.

[0047] R⁴ is cycloalkylalkylene having 5-12 carbon atoms, preferably,for example, cyclopentylmethylene, cyclohexylmethylene,cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.

[0048] R⁴ is alternatively cycloalkyl, preferably having 5-7 carbonatoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl orcycloheptyl.

[0049] R⁵ is preferably, for example, OCH₂COOH, OCH₂COOA,S(O)_(m)CH₂COOH or S(O)_(m)CH₂COOA.

[0050] Hal is preferably F, Cl or Br, but also 1.

[0051] The radicals R¹ and R² may be identical or different and arepreferably located in the 3- or 4-position of the phenyl ring. They are,for example, in each case independently of one another, H, OH, alkyl, F,Cl, Br or I or together are alkylene, such as, for example, propylene,butylene or pentylene, furthermore ethyleneoxy, methylenedioxy orethylenedioxy. They are preferably also in each case alkoxy, such as,for example, methoxy, ethoxy or propoxy.

[0052] The term solvates is taken to mean hydrates or, for example,alcoholates.

[0053] For the entire invention, all radicals which occur more than oncemay be identical or different, i.e. are independent of one another.

[0054] Accordingly, the invention relates in particular to the compoundsof the formula I in which at least one of the said radicals has one ofthe preferred meanings indicated above, Some preferred groups ofcompounds may be expressed by the following sub-formulae la to If, whichconform to the formula I and in which the radicals not designated ingreater detail are as defined under the formula I, but in which

[0055] in Ia X is R³ which is substituted by O(CH₂),COOH,O(CH₂)_(n)COOA, O(CH₂)_(n)CONH₂, O(CH₂)_(n)CONHA,. O(CH₂)_(n)CONA₂ orO(CH₂)_(n)CN, S(O)_(m)(CH₂)_(n)COOH, S(O),(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)CONH₂, S(O)_(m)(CH₂)_(n)CONHA, S(O)_(m)(CH₂)_(n)CONA₂or S(O)_(m)(CH₂)_(n)CN;:

[0056] in Ib R¹ and R² are each, independently of one another, Hal, OHor OA,

[0057] X is R³ which is substituted by O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA;

[0058] in Ic R¹ and R² are each, independently of one another, Hal, OHor OA,

[0059] X is R³ which is substituted by O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA,

[0060] R³ is methylene, ethylene or propylene;

[0061] in Id R¹ and R² are each, independently of one another, Hal, OHor OA,

[0062] R¹ and R² together are alkylene having 3-5 carbon atoms,—O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O,

[0063] X is R³ which is substituted by O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA,

[0064] R³ is methylene, ethylene or propylene;

[0065] in Ie R¹ and R² are each, independently of one another, H, Hal,A, NO₂, OH or OA,

[0066] R¹ and R² together are alkylene having 3-5 carbon atoms,—O—CH₂—CH₂—, —O—C H₂—O—or —O—C H₂—C H₂—O,

[0067] X is R3 which is substituted by O(CH₂),COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA,

[0068] R³ is methylene, ethylene or propylene,

[0069] A is alkyl having 1-6 carbon atoms or CF₃;

[0070] in If R¹ and R² are each, independently of one another, H, Hal,A, NO₂, OH or OA,

[0071] R¹ and R² together are —O—CH₂—O— or —O—CH₂—CH₂—O—,

[0072] X is R³ which is substituted by O(CH₂),COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA,

[0073] R³ is methylene, ethylene or propylene,

[0074] A is alkyl having 1-6 carbon atoms or CF₃;

[0075] and their physiologically acceptable salts and/or solvates.

[0076] The compounds of the formula I and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

[0077] In the compounds of the formulae II or III, R¹, R² and X have themeanings indicated, in particular the preferred meanings indicated.

[0078] If L is a reactive esterified OH group, this is preferablyalkylsulfonyloxy having 1-6 carbon atoms (preferably methylsuffonyloxy)or arylsuffonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy, furthermore also 2-naphthalenesulfonyloxy).

[0079] The compounds of the formula I can preferably be obtained byreacting compounds of the formula II with compounds of the formula III.

[0080] If desired, the starting materials can also be formed in situ bynot isolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the Formula I.

[0081] On the other hand, it is possible to carry out the reactionstepwise.

[0082] The starting compounds of the formula II and III are generallyknown. If they are not known, they can be prepared by methods known perse. Compounds of the formula II can be obtained, for example, from thecorresponding hydroxypyrimidines, which are built up from thiophenederivatives and CN-substituted alkylenecarboxylic acid esters (Eur. J.Med. Chem. 23, 453 (1988)), by reaction with POCl₃.

[0083] The hydroxypyrimidinesare prepared either by dehydrogenation ofcorresponding tetrahydrobenzothienopyrimidine compounds or by thecyclisation of 2-aminobenzothiophene-3-carboxylic acid derivatives usingaldehydes or nitrites, which is conventional for the preparation ofpyrimidine derivatives (for example Houben-Weyl E9b/2).

[0084] In detail, the reaction of the compounds of the formula II withthe compounds of the formula III is carried out in the presence orabsence of an inert solvent at temperatures between about −20 and about150°, preferably between 20 and 100°.

[0085] The addition of an acid-binding agent, for example an alkali oralkaline earth metal hydroxide, carbonate or bicarbonate or another saltof a weak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium or calcium, or the addition of an organic base, suchas triethylamine, dimethylamine, pyridine or quinoline or of an excessof the amine component, may be favourable.

[0086] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol ethanol, iso-propanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF);nitrites, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters,such as ethyl acetate, or mixtures of the said solvents.

[0087] It is furthermore possible to convert a radical X in a compoundof the formula I into another radical X, for example by hydrolysing anester or a cyano group to give a COOH group.

[0088] Ester groups can be saponified, for example, using NaOH or KOH inwater, water/THF or water/dioxane at temperatures between 0 and 1000.Carboxylic acids can be converted into the corresponding carboxylic acidchlorides, for example using thionyl chloride, and these can beconverted into carboxamides. Elimination of water therefrom in a knownmanner gives carbonitriles.

[0089] An acid of the formula I can be converted into the associatedacid-addition salt using a base, for example by reaction of equivalentamounts of the acid and the base in an inert solvent, such as ethanol,followed by evaporation. Suitable bases for this reaction are, inparticular, those which give physiologically acceptable salts.

[0090] Thus, the acid of the formula I can be converted into the,corresponding metal salt, in particular alkali metal or alkaline earthmetal salt, or into the corresponding ammonium salt using a base (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Also suitable for this reaction are, inparticular, organic bases which give physiologically acceptable salts,such as, for example, ethanolamine.

[0091] On the other hand, a base of the formula I can be converted intothe associated acid-addition salt using an acid, for example by reactionof equivalent amounts of the base and the acid in an inert solvent, suchas ethanol, followed by evaporation. Suitable acids for this reactionare, in particular, those which give physiologically acceptable acids.Thus, it is possible to use inorganic acids, for example sulfuric acid,nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromicacid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, orlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purificatior ofthe compounds of the formula I.

[0092] The invention furthermore relates to the use of the compounds ofthe formula I and/or their physiologically acceptable salts for theproduction of pharmaceutical preparations, in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semiliquid excipient or assistantand optionally in combination with one or more further activeingredients.

[0093] The invention also relates to medicaments of the formula I andtheir physiologically acceptable salts as phosphodiesterase Vinhibitors.

[0094] The invention furthermore relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

[0095] These preparations can be used as medicaments in human orveterinary medicine. Suitable excipients are organic or inorganicsubstances which are suitable for enteral (for example oral), parenteralor topical administration and do no react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose or starch, magnesium stearates, talc or vaseline. Suitablefor oral administration are, in particular, tablets, pills, coatedtablets, capsules, powders, granules, syrups, juices or drops, suitablefor rectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The preparationsindicated may be sterilised and/or comprise assistants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

[0096] The compounds of the formula I and their physiologicallyacceptable salts can be employed for combating illnesses in which anincrease in the cGMP (cycloguanosine monophosphate) level results ininflammation inhibition or prevention and muscle relaxation. Thecompounds according to the invention are used in particular in thetreatment of illnesses of the cardiovascular system and for thetreatment and/or therapy of impotence.

[0097] The invention relates to the use of the compounds of the formulaI and their physiologically acceptable salts and/or solvates for thepreparation of a medicament for the treatment of angina, high bloodpressure, high pulmonary pressure, congestive heart failure,atherosclerosis, conditions involving reduced passage through heartvessels, peripheral vascular diseases, strokes, bronchitis, allergicasthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowelsyndrome, tumours, renal insufficiency, liver cirrhosis and for thetreatment of female sexual disorders.

[0098] In general, the substances are preferably administered in dosesof between about 1 and 500 mg, in particular between 5 and 100 mg perdosage unit. The daily dose is preferably between about 0.02 and 10mg/kg of body weight. However, the specific dose for each patientdepends on a wide variety of factors, for example on the efficacy of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and method of administration, onthe excretion rate, medicament combination and severity of theparticular illness to which the therapy applies. Oral administration ispreferred.

[0099] Above and below, all temperatures are given in ° C. In theexamples below, “conventional work-up” means that water is added ifnecessary, a pH of from 2 to 10, depending on the constitution of theend product, is set if necessary, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation.

[0100] Mass spectrometry (MS): EI (electron impact ionisation) M⁺

[0101] FAB (fast atom bombardment) (M+H)⁺

EXAMPLE 1

[0102] 357 ml of cyclohexanone are added dropwise at room temperature toa suspension of 115 g of sulfur and 300 ml of methyl cyanoacetate in 500ml of methanol. 350 ml of diethylamine are then slowly added, duringwhich the temperature is held at a maximum of 500. The mixture isstirred for a further 12 hours and cooled to 4°, and the crystals areseparated off and washed with ice-cold methanol. Drying gives 580 g ofmethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (“AA”),m.p. 130°.

[0103] 40 ml of chloroacetonitrile are added to a solution of 106 g of“AA” in 600 ml of dioxane, and HCl is passed in at 40-500 for 3 hourswith stirring. The mixture is stirred for a further 2 hours, the solventis removed, and the mixture is subjected to conventional work-up, giving125 g of2-chloromethyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin4-one(“AB”), m.p. 285-2860.

[0104] 1.7 g of sodium hydride (50% suspension) are added to a solutionof 5.0 g of “AB” and 2.89 of butyl glycolate in 100 ml of THF, and themixture is refluxed for 3 hours. The solvent is removed, and the mixtureis subjected to conventional work-up, giving 5.09 of butyl(4-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate(“AC”). 1 ml of DMF is added to a solution of 5.0 g of “AC” in 50 ml ofthionyl chloride, and the mixture is stirred at 450 for 2 hours. Afterthe solvent has been removed, the mixture is subjected to conventionalwork-up, giving 4.5 g of butyl(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate(“AD”).

EXAMPLE 2

[0105] The compound butyl(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy)acetate(“AE”) is obtained analogously by reaction of “AA” withchloropropionitrile and further reaction analogously to Example 1.

EXAMPLE 3

[0106] A solution of 4.5 g of “AD” and 4.5 g of3-chloro-4-methoxybenzylamine in 30 ml of 1-methylpyrrolidone is heatedat 1000 for 1 hour. The solvent is removed, and the mixture is subjectedto conventional work-up, giving 1.8 g of butyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate.

[0107] The compound butyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylethoxy]acetateis obtained analogously from “AE”.

[0108] Analogous reaction of

[0109] 3,4-methylenedioxybenzylamine,

[0110] 3,4-dimethoxybenzylamine,

[0111] 4-methoxybenzylamine,

[0112] 3,4-dichlorobenzylamine,

[0113] 4-chlorobenzylamine,

[0114] 4-methylbenzylamine,

[0115] 4-fluorobenzylamine,

[0116] benzylamine,

[0117] 3-chloro-4-nitrobenzylamine,

[0118] 2,4-dichlorobenzylamine,

[0119] 2-chloro-4-fluorobenzylamine,

[0120] 3-fluorobenzylamine,

[0121] 2-methoxybenzylamine,

[0122] 2-chlorobenzylamine,

[0123] 3,5-di(trifluoromethoxy)benzylamine,

[0124] with “AD” or “AE” gives the following compounds

[0125] butyl [4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0126] butyl[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0127] butyl[4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0128] butyl[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0129] butyl[4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0130] butyl[4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0131] butyl[4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-dlpyrimidin-2-ylmethoxy]acetate,

[0132] butyl(4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethoxy)acetate,

[0133] butyl[4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxylacetate,

[0134] butyl [4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0135] butyl[4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0136] butyl[4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0137] butyl[4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-dlpyrimidin-2-ylmethoxy]acetate,

[0138] butyl[4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]acetate,

[0139] butyl{4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-dlpyrimidin-2-ylmethoxy}acetate,

[0140] butyl[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0141] butyl [4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0142] butyl[4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0143] butyl [4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0144] butyl[4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-(2,3-dlpyrimidin-2-ylethoxy]acetate

[0145] butyl[4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0146] butyl[4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-dipyrimidin-2-ylethoxy]acetate,

[0147] butyl(4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy)acetate,

[0148] butyl[4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0149] butyl [4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5-thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0150] butyl[4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0151] butyl[4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0152] butyl[4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0153] butyl[4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]acetate,

[0154] butyl{4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylethoxy}acetate.

EXAMPLE 4

[0155] Reaction of “AB” with ethyl thioglycolate analogously to Example1 gives the compound ethyl(4-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfanyl)acetate(“AF”), m.p. 172°.

[0156] A mixture of 4.0 g of “AF”, 50 ml of phosphoryl chloride and 1 mlof N-ethyldiisopropylamine is stirred at 90° for 2 hours. After removalof the phosphoryl chloride, the mixture is subjected to conventionalwork-up, giving 2.5 g of ethyl(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno(2,3-d]-pyrimidin-2-ylmethylsulfanyl)acetate(“AG”).

[0157] The following benzylamine derivatives are obtained from “AG”analogously to Example 3

[0158] ethyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,m. p. 98-99°;

[0159] ethyl[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,ethyl[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno-2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0160] ethyl[4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0161] ethyl[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0162] ethyl[4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0163] ethyl[4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0164] ethyl[4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0165] ethyl(4-benzylamino-5,6,7,8-tetrahydrobenzo(4,5]thieno[2,3-c]-pyrimidin-2-ylmethylsulfanyl)acetate,

[0166] ethyl[4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0167] ethyl [4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0168] ethyl[4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-dipyrimidin-2-ylmethylsulfanyl]acetate,

[0169] ethyl[4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0170] ethyl[4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0171] ethyl[4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,

[0172] ethyl {4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl}acetate.

EXAMPLE 5

[0173] 1.1 g of hydrogen peroxide (30%) are added to a solution of 2.0 gof ethyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetatein 50 ml of glacial acetic acid, and the mixture is stirred at roomtemperature for 3 hours.

[0174] The mixture is subjected to conventional work-up, giving 1.7 g ofethyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetate,m.p. 158-160°.

[0175] The following compounds are obtained analogously from thesulfanyl derivatives obtained in Example 4

[0176] ethyl [4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0177] ethyl [4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0178] ethyl[4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0179] ethyl [4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0180] ethyl[4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0181] ethyl[4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0182] ethyl[4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0183] ethyl(4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl)acetate,

[0184] ethyl[4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0185] ethyl(4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0186] ethyl[4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0187] ethyl[4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0188] ethyl[4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0189] ethyl[4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]acetate,

[0190] ethyl{4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl}acetate.

EXAMPLE 6

[0191] A solution of 1.8 g of butyl[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy]acetatein 60 ml of ethylene glycol monoethyl ether and 20 ml of 2M NaOH isstirred in a steam bath for 30 minutes.

[0192] The mixture is subjected to conventional work-up, giving 1.7 g of[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid, m.p. 136-137°.

[0193] The resultant compound is dissolved at elevated temperature is 20ml of isopropanol and 0.3 g of ethanolamine and cooled, and ether isadded. The precipitated crystals are separated off, giving 1.7 g of[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy]aceticacid, ethanolamine salt, m.p. 148-149°.

[0194] The following carboxylic acid derivatives are obtainedanalogously from the esters obtained in Example 3

[0195][4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0196][4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0197][4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0198][4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0199][4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-]-pyrimidin-2-ylmethoxy]aceticacid,

[0200][4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethoxy]aceticacid,

[0201][4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethoxy]aceticacid,

[0202](4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)aceticacid,

[0203][4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0204][4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0205][4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethoxy]aceticacid,

[0206][4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethoxy]aceticacid,

[0207][4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo(4,5]thieno-[2,3-dlpyrimidin-2-ylmethoxy]aceticacid,

[0208][4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethoxy]aceticacid,

[0209] {4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy}aceticacid,

[0210][4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]aceticacid, ethanolamine salt, 139-140°;

[0211][4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0212][4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0213][4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-dipyrimidin-2-ylethoxy]aceticacid,

[0214][4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0215][4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy]aceticacid,

[0216][4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy]aceticacid,

[0217][4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy]aceticacid,

[0218](4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylethoxy)aceticacid,

[0219][4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0220][4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0221][4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0222][4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy]aceticacid,

[0223][4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylethoxy]aceticacid,

[0224][4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylethoxy]aceticacid,

[0225]{4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidin-2-ylethoxy}aceticacid.

EXAMPLE 7

[0226] The following carboxylic acid derivatives are obtainedanalogously to Example 6 by ester cleavage from the ethyl esterderivatives obtained in Examples 4 and 5 using NaOH in methanol

[0227][4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-dipyrimidin-2-ylmethylsulfanyl]aceticacid, ethanolamine salt, m.p. 161-162°;

[0228][4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0229][4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0230][4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0231][4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0232][4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno(2,3-d]-pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0233][4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfanyl]acetic acid,

[0234][4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0235](4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl)aceticacid,

[0236][4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0237][4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0238][4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0239][4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0240][4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo(4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0241][4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfanyl]aceticacid,

[0242] {4-[3,5-di(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo-[

[0243] 4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfanyl}acetic acid,[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno(2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid, ethanolamine salt, amorphous,

[0244] [4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0245][4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0246][4-(4-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0247] [4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0248][4-(4-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0249][4-(4-methylbenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0250][4-(4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0251](4-benzylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl)aceticacid,

[0252][4-(3-chloro-4-nitrobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0253][4-(2,4-dichlorobenzylamino)-5,6,7,8-tetrahydrobenzo(4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0254][4-(2-chloro-4-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]-thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0255][4-(3-fluorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0256][4-(2-methoxybenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0257][4-(2-chlorobenzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-2-ylmethylsulfinyl]aceticacid,

[0258] {4-[3,5-d i(trifluoromethoxy)benzylamino]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethylsulfinyl}acetic acid.

[0259] The examples below relate to pharmaceutical preparations,

EXAMPLE A Injection vials

[0260] A solution of 100 g of an active ingredient of the formula I and5 g of disodium hydrogen phosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

[0261] A mixture of 20 g of an active ingredient of the formula I ismelted with 100 g of soya lecithin and 1400 g of cocoa butter, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

[0262] A solution is prepared from 1 g of an active ingredient of theformula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

[0263] 500 mg of an active ingredient of the formula I are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

[0264] A mixture of 1 kg of an active ingredient of the formula I, 4 kgof lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is pressed to give tablets in a conventional mannerin such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated tablets

[0265] Tablets are pressed analogously to Example E and subsequentlycoated in a conventional manner with a coating of sucrose, potatostarch, talc, tragacanth and dye.

EXAMPLE G Capsules

[0266] 2 kg of an active ingredient of the formula I are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

[0267] A solution of 1 kg of an active ingredient of the formula I in 60l of bidistilled water is sterile filtered transferred into ampociles,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation spray

[0268] 14 g of an active ingredient of the formula I are dissolved in 10l of isotonic NaCl solution, and the solution is transferred intocommercially available spray containers with a pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1. Compounds of the formula i

in which R¹ and R² are each, independently of one another, H, A, OH, OA,NO₂ or Hal, R¹ and R² together are alternatively alkylene having 3-5carbon atoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, X ismono-R⁵-substituted R³ or R⁴, R³ is linear or branched alkylene having1-10 carbon atoms, in which one or two CH₂ groups may be replaced by—CH═CH— groups, O, NH or NA, R⁴ is cycloalkyl or cycloalkylalkylenehaving 5-12 carbon atoms, R⁵ is O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,O(CH₂)_(n)CONH₂, O(CH₂)_(n)CONHA, O(CH₂)_(n)CONA₂ or O(CH₂)NCN,S(O)_(m)(CH₂)_(n)COOH, S(O)_(m)(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)CONH₂,S(O)_(m)(CH₂)_(n)CONHA, S(O)_(m)(CH₂)_(n)CONA₂ or S(O)_(m)(CH₂)_(n)CN mis 0,1 or 2, n is 1 or 2, A is alkyl having 1 to 6 carbon atoms, and Halis F, Cl, Br or I, and their physiologically acceptable salts and/orsolvates:
 2. Compounds according to claim 1, in which X is R³ which issubstituted by O(CH₂),COOH, O(CH₂)_(n)COOA, O(CH₂)_(n)CONH₂,O(CH₂)_(n)CONHA, O(CH₂)_(n)CONA₂ or O(CH₂)_(n)CN, S(O)_(m)(CH₂)_(n)COOH,S(O)_(m)(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)CONH₂, S(O)_(m)(CH₂)_(n)CONHA,S(O)_(m)(CH₂)_(n)CONA₂ or S(O)_(m)(CH₂)_(n)CN, and their physiologicallyacceptable salts and/or solvates.
 3. Compounds according to claim 1, inwhich R¹ and R² are each, independently of one another, Hal, OH or OA, Xis R³ which is substituted by O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA, and theirphysiologically acceptable salts and/or solvates.
 4. Compounds accordingto claim 1, in which R¹ and R² are each, independently of one another,Hal, OH or OA, X is R³ which is substituted by O(CH₂)_(n)COOH,O(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA, R³ ismethylene, ethylene or propylene, and their physiologically acceptablesalts and/or solvates.
 5. Compounds according to claim 1, in which R¹and R² are each, independently of one another, Hal, OH or OA, R¹ and R²together are alkylene having 3-5 carbon atoms, —O—CH₂—CH₂—, —O—CH₂—O— or—O—CH₂—CH₂—O, X is R³ which is substituted by O(CH₂)_(n)COOH,O(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA, R³ ismethylene, ethylene or propylene, and their physiologically acceptablesalts and/or solvates.
 6. Compounds according to claim 1, in which R¹and R² are each, independently of one another, H, Hal, A, NO₂, OH or OA,R¹ and R² together are alkylene having 3-5 carbon atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O, X is R³ which is substituted byO(CH₂)_(n)COOH, O(CH₂)_(n)COOA, S(O)_(m)(CH₂)_(n)COOH orS(O)_(m)(CH₂)_(n)COOA, R³ is methylene, ethylene or propylene, A isalkyl having 1-6 carbon atoms or CF₃, and their physiologicallyacceptable salts and/or solvates.
 7. Compounds according to claim 1, inwhich R¹ and R² are each, independently of one another, H, Hal, A, NO₂,OH or OA, R¹ and R² together are —O—CH₂—O— or —O—CH₂—CH₂—O—, X is R³which is substituted by O(CH₂)_(n)COOH, O(CH₂)_(n)COOA,S(O)_(m)(CH₂)_(n)COOH or S(O)_(m)(CH₂)_(n)COOA, R³ is methylene,ethylene or propylene, A is alkyl having 1-6 carbon atoms or CF₃, andtheir physiologically acceptable salts and/or solvates.
 8. Compoundsaccording to claim 1, (a)2-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[4,5]-benzothieno[2,3-d]pyrimidin-2-ylmethoxy]aceticacid; (b)2-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[4,5]-benzothieno[2,3-d]pyrimidin-2-ylmethylsulfanyl]acetic acid; (c)2-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[4,5]-benzothieno(2,3-d]pyrimidin-2-ylmethylsulfinyl]aceticacid; (d)2-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[4,5]-benzothieno[2,3-d]pyrimidin-2-ylethoxy]aceticacid; and their physiologically acceptable salts and/or solvates. 9.Process for the preparation of compounds of the formula I according toclaim 1 and their salts, characterised in that a) a compound of theformula II

 in which X is as defined above, and L is Cl, Br, OH, SCH₃ or a reactiveesterified OH group, is reacted with a compound of the formula III

 in which R¹ and R² are as defined above, or b) a radical X in acompound of the formula I is converted into another radical X by, forexample, hydrolysing an ester group to a COOH group or converting a COOHgroup into an amide or into a cyano group, and/or in that a compound ofthe formula I is converted into one of its salts.
 10. Compounds of theformula I according to claims 1 to 8 and their physiologicallyacceptable salts and solvates as medicaments.
 11. Medicaments accordingto claim 10 for the inhibition of phosphodiesterase V.
 12. Medicamentsaccording to claim 10 or 11 for combating illnesses of thecardiovascular system and for the treatment and/or therapy of impotence.13. Medicaments according to claim 10, 11 or 12 for the treatment ofangina, high blood pressure, high pulmonary pressure, congestive heartfailure, atherosclerosis, conditions of reduced passage through theheart vessels, peripheral vascular diseases, strokes, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritablebowel syndrome, tumours, renal insufficiency, liver cirrhosis and forthe treatment of female sexual disorders.
 14. Pharmaceutical preparationcomprising at least one medicament according to one of claims 10 to 13and optionally excipients and/or assistants and optionally other activeingredients.
 15. Use of compounds according to claims 1 to 8 and/ortheir physiologically acceptable salts or solvates for the preparationof a medicament for combating illnesses of the cardiovascular system andfor the treatment and/or therapy of impotence.
 16. Use of compoundsaccording to claims 1 to 8 and/or their physiologically acceptable saltsor solvates for the preparation of a medicament for the treatment ofangina, high blood pressure, high pulmonary pressure, congestive heartfailure, atherosclerosis, conditions of reduced passage through theheart vessels, peripheral vascular diseases, strokes, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritablebowel syndrome, tumours, renal insufficiency, liver cirrhosis and forthe treatment of female sexual disorders.